There has been a recent expansion in the distribution and the incidence of leishmaniasis. Visceral leishmaniasis is particularly troublesome as it causes most fatalities. India, Nepal, Bangladesh, Sudan and Brazil harbor 90% of the worldwide reported VL cases. Amongst the millions at risk in India, the state of Bihar accounts for nearly 90% of cases, followed by the states of West Bengal, Jharkhand and Eastern Uttar Pradesh. This proposed Tropical Medicine Research Center is divided into 3 projects that will address epidemiological, clinical, immunological and genetic factors that influence the prevalence, distribution and pathogenesis of visceral leishmaniasis in individuals and communities in Bihar State in India. The individual projects that make up this TMRC are also designed to provide new data that will be more broadly applicable to the continuing development of control programs in the other major global foci of disease, including development of novel vaccines and diagnostic aids. Themes of the three major projects are: Project 1: Clinical and epidemiological studies of Visceral Leishmaniasis in Bihar, India: Goals of this project are to provide the epidemiological and clinical evidence that is required to guide efforts to eliminate or control visceral leishmaniasis in the state of Bihar, India, and to provide epidemiological data that will more broadly inform future control programs including development of novel vaccines and diagnostic aids. Project 2: The role of regulatory T cell subsets and cytokines in the pathogenesis of human VL in Bihar, India. This project is a focused study that will investigate the role of regulatory T cells and suppressive cytokines in the pathogenesis of human visceral leishmaniasis, with a view toward the development of immune-based therapies that will reverse the immunosuppression associated with active disease. Project 3: Genetic risk factors for Visceral Leishmaniasis in Bihar, India. This project will address genetic factors that underly genetic susceptibility to visceral leishmaniasis, with the purpose of identifying genes/ mechanisms/ pathways that contribute to the pathogenesis of disease. The TMRC will bring together a unique combination of epidemiologists, clinicians, immunologists and molecular geneticists to tackle the problem of visceral leishmaniasis in one of the major global foci of this fatal disease. PROJECT 1: Clinical and epidemiological studies of Visceral Leishmaniasis in Bihar, India (Singh, S. P.) PROJECT 1 DESCRIPTION (provided by applicant): Lay statement: Visceral leishmaniasis (VL) is a parasitic disease that is fatal if untreated. Several hundred thousand people are affected in the Indian subcontinent. Most are poor and depend on public funds or charity for treatment. Disease control is based on early diagnosis and treatment, and control of sandflies that transmit disease. Control efforts to date have given only temporary reprieve, with periodic rebound of major epidemics. This is because there are gaps in our understanding of the dynamics of disease transmission. This study is designed to identify these factors, and to evaluate novel diagnostics and vaccine candidates that have arisen through genomic sequencing of the parasite. The study will provide new knowledge and tools to allow regional governments to achieve their aim of disease control by 2015. Project description: VL in India is patchy in distribution. The determinants of disease transmission at a village and household level are not well understood. Subclinical infection is thought to play a significant role in disease transmission, but markers of subclinical infection have yet to be validated. We don't fully understand why only a small proportion of infected subjects develop clinical disease. To gain a better understanding of disease dynamics and transmission, this study will undertake (1) an exhaustive population survey of 50,000 persons for two consecutive years using household interviews, CIS technology, remote sensing data and multi-level modelling, to identify the ecological risk markers that will permit better targeting of control interventions;(2) a nested case control study to document the modifiable risk factors (e.g. nutritional) and risk markers (clinical, genetic, immunological) for VL at household and individual level, with two annual rounds of sero-survey allowing us to document incident leishmanial infections, and a 3-year longitudinal follow-up to document development of full blown VL;(3) evaluation of existing (rK39 ELISA, Direct Agglutination Test, LST) markers of infection against standard Western blot and qualitative kDNA PCR and new Quantiferon assays for T cell responses;(4) evaluation of novel (Leishmania donovanicomplex specific genes) markers using qualitative and quantitative PCR, ELISA and T-cell assays;and (5) immune profiling of novel vaccine candidate in patients and endemic controls. The results will inform policy and practice for disease control in the Indian sub-continent, and add to global understanding of VL disease.